ES2304022T3 - TIAZOLIL-DIHIDRO-INDAZOLES. - Google Patents

Abstract

Compounds of the general formula (1), (See formula) where R1 is selected from the group consisting of -NHRc, -NHC (O) Rc, -NHC (O) ORc, -NHC (O) NRcRc and -NHC (O) SRc; R2 is a radical that can be substituted with one or more R4, selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-10 aryl, C7-16 arylalkyl and 5-6 heteroaryl 10 members; R3 is a radical that may be substituted with one or more Re and / or Rf, chosen from the group consisting of C6-10 aryl and 5-10 membered heteroaryl; R4 is a radical chosen from the group consisting of Ra, Rb and Ra substituted with one or more same or different Rc and / or Rb; each Ra, independently of each other, is selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C6-10 aryl, C7-16 arylalkyl, 2-6 membered heteroalkyl, 3-heterocycloalkyl -8 members, 4-14 membered heterocycloalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each Rb is a suitable radical and independently selected from the group consisting of = O, -ORc, C1-3 haloalkyloxy, -OCF3, = S, -SRc, = NRc, = NORc, -NRcRc, halogen, -CF3, - CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) Rc, -S (O) 2Rc, -S (O) 2ORc, -S (O) NRcRc , -S (O) 2NRcRc, -OS (O) Rc, -OS (O) 2Rc, -OS (O) 2ORc, -OS (O) 2NRcRc, -C (O) Rc, -C (O) ORc, -C (O) NRcRc, -C (O) N (Rg) NRcRc, -C (O) N (Rg) ORc, -CN (Rg) NRcRc, -OC (O) Rc, -OC (O) ORc, -OC (O) NRcRc, -OCN (Rg) NRcRc, -N (Rg) C (O) Rc, -N (Rg) C (S) Rc, -N (Rg) S (O) 2Rc, -N ( Rg) S (O) 2NRcRc, -N [S (O) 2] 2Rc, -N (Rg) C (O) ORc, -N (Rg) C (O) NRcRc and -N (Rg) CN (Rg) NRcRc; each Rc, independently of one another, is hydrogen or a radical optionally substituted with one or more equal or different Rd and / or Re, selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C6- aryl 10, C7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each Rd, independently of each other, is hydrogen or a radical optionally substituted with one or more same or different Re and / or Rf, selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C6- aryl 10, C7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; Each Re is a suitable radical and independently selected from the group consisting of = O, -ORf, C1-3 haloalkyloxy, -OCF3, = S, -SRf, -NRf, = NORf, -NRfRf, halogen, -CF3, - CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) Rf, -S (O) 2Rf, -S (O) 2ORf, -S (O) NRfRf , -S (O) 2NRfRf, -OS (O) Rf, -OS (O) 2Rf, -OS (O) 2ORf, -OS (O) 2NRfRf, -C (O) Rf, -C (O) ORf, -C (O) NRfRf, -CN (Rg) NRfRf, -OC (O) Rf, -OC (O) ORf, -OC (O) NRfRf, -OCN (Rg) NRfRf, -N (Rg) C (O ) Rf, -N (Rg) C (S) Rf, -N (Rg) S (O) 2Rc, -N (Rg) C (O) ORf, -N (Rg) C (O) NRfRf and -N ( Rg) CN (Rg) NRfRf; each Rf, independently of one another, is hydrogen or a radical optionally substituted with one or more same or different Rg, selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C6-10 aryl, C7 arylalkyl -16, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered heterocycloalkyl alkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each Rg, independently of one another, is hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C6-10 aryl, C7-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, heterocycle - 4-14 membered alkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; which may be in the form of their tautomers, their racemates, their enantiomers, their diastereoisomers and mixtures thereof, as well as, where appropriate, their pharmacologically safe addition salts.

Description

Thiazolyl-dihydro-indazoles.

The present invention relates to new thiazolyl dihydro-indazoles of the general formula (1)

one

where the radicals R1 up to R 3 have the meanings cited in the claims and in the description, to its isomers, to methods to prepare these thiazolyl-dihydro-indazoles and their use as medicines.

Background of the present invention

Protein and lipid phosphorylation is a important cell regulation mechanism that plays a role in multiple biological processes, such as p. ex. cell proliferation, differentiation, apoptosis, metabolism, inflammation, immuno-reactions and angiogenesis. In the genome human there are more than 500 encoded kinases. Generally, the Tyrosine protein kinases are stimulated by factors of growth or other mitogenic signals and phosphorylate proteins that initiate fast signal transmissions. The protein kinases of serine / threonine phosphorylate mostly interconnecting proteins and amplify intracellular signals. The lipid kinases are also important points of connection between the intracellular signal pathways that link various biological processes

Numerous protein kinases have proven to be appropriate target molecules for therapeutic intervention in various indications, such as p. ex. cancer diseases inflammatory and autoimmune. As a large percentage of genes identified to date as participants in the formation of cancers encode kinases, these enzymes constitute molecules especially interesting target for cancer therapy.

Phosphatidylinositol-3-kinases (PI3 kinases) are a subfamily of lipid kinases, which catalyze the transfer of a phosphate radical to the 3 'position of the phosphoinositide inositol ring. They have an important role in many cellular processes, such as p. ex. those of cell growth and differentiation, the control of cytoskeletal variations and the regulation of intracellular transport processes. PI3 kinases can be divided into different classes, according to their specificity in vitro for certain phosphoinositide substrates.

Of the members of class I of PI3 kinases, PI3α, β and δ kinases (class IA) are activated primarily by tyrosine kinase receptors (RTKs) or by soluble tyrosine kinases. Instead, PI3γ kinase (class IB) is mainly activated by subunits Gβ [gamma] released from heterothermal G proteins after heptahelicoidal receptor activation. Of this different coupling to cell surface receptors - combined with a more or less restrictive expression - they inevitably result very different tasks and functions of the 4th class I of PI3 kinases in the intact organism.

Many independent findings support the participation of class IA PI3 kinases in processes uncontrolled growth and cell differentiation. The first Proven PI3 kinase activity was associated with the activity Transformer of viral oncogenes, such as p. ex. the average T antigen of polyoma virus, Src tyrosine kinases or growth factors activated (Workman, Biochem Soc Trans. 2004; 32 (Pt 2): 393-6). In many tumors, such as p. ex. cancer of breast, ovarian carcinoma or also pancreatic carcinoma, it finds an overactivity of the Akt / PKB, which is activated directly by the lipid products of the PI3 kinases of the class I, thus transmitting the signals to the cell. Also I know recently discovered that the PIK3CA gene -coder of the p110 subunit of PI3Kα- has a high frequency of mutation in various types of tumors, such as p. ex. carcinomas of colon, breast or lung, some of which can be characterized as representative of activating mutations.

In WO 0 303 618 and US 2002/151544 patents already PI3 kinase inhibitors have been described.

Detailed description of the present invention

Now it has been surprisingly found that compounds of the general formula (1) whose radicals R1 up to R3 have the meanings indicated below act as specific cell cycle kinase inhibitors. So the compounds of the present invention can be used, for example, to treat diseases that are related to the activity of specific cell cycle kinases and characterized by a excessive or abnormal cell proliferation.

The present invention relates to compounds of the general formula (1)

2

where

quad

R1 is chosen from the group consisting of -NHR c, -NHC (O) R c, -NHC (O) OR c, -NHC (O) NR c R c and -NHC (O) SR c;

quad

R2 is a radical that can be substituted with one or more R 4, chosen from the group consisting of alkyl C 1-6, C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, aryl C 6-10 and 5-10 heteroaryl members;

quad

R3 is a radical that can be substituted with one or more R e and / or R f, chosen from the group consisting of C 6-10 aryl and heteroaryl of 5-10 members;

quad

R 4 is a radical chosen from the group consisting of R a, R b and R a substituted with one or more R c and / or R b the same or different;

quad

each R a, independently of each other, is chosen from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 alkylalkyl alkyl, C 6-10 aryl, arylalkyl C 7-16, 2-6 heteroalkyl members, 3-8 hetero heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-10 membered heteroaryl and heteroarylalkyl of 6-16 members;

quad

each R b is a suitable and chosen radical independently of each other from the group consisting of = O, -OR c, C 1-3 haloalkyloxy, -OCF 3, = S, -SR c, = NR c, = NOR c, -NR c R c, halogen, -CF 3, -CN, -NC, -OCN, -SCN, -NO, -NO_ {2}, = N_ {{}}, -N_ {3}, -S (O) R c, -S (O) 2 R c, -S (O) 2 OR c, -S (O) NR c R c, -S (O) 2 NR c R c, -OS (O) R c, -OS (O) 2 R c, -OS (O) 2 OR c, -OS (O) 2 NR c R c, -C (O) R c, -C (O) OR c, -C (O) NR c R c, -C (O) N (R g) NR c R c, -C (O) N (R g) OR c, -CN (R g) NR c R c, -OC (O) R c, -OC (O) OR c, -OC (O) NR c R c, -OCN (R g) NR c R c, -N (R g) C (O) R c, -N (R g) C (S) R c, -N (R g) S (O) 2 R c, -N (R g) S (O) 2 NR c R c, -N [S (O) 2] 2 R c, -N (R g) C (O) OR c, -N (R g) C (O) NR c R c and -N (R g) CN (R g) NR c R c;

quad

each R c, independently of each other, is hydrogen or a radical optionally substituted with one or more R d and / or R e same or different, selected from the group formed by C 1-6 alkyl, cycloalkyl C 3-8, cycloalkylalkyl C 4-11, aryl C 6-10, C 7-16 arylalkyl, heteroalkyl of 2-6 members, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkylalkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

quad

each R d, independently of each other, is hydrogen or a radical optionally substituted with one or more R e and / or R f same or different, selected from the group formed by C 1-6 alkyl, cycloalkyl C 3-8, cycloalkylalkyl C 4-11, aryl C 6-10, C 7-16 arylalkyl, heteroalkyl of 2-6 members, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkylalkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

quad

each R e is a suitable and chosen radical independently of each other from the group consisting of = O, -OR f, C 1-3 haloalkyloxy, -OCF 3, = S, -SR f, -NR f, = NOR f, -NR f R f, halogen, -CF 3, -CN, -NC, -OCN, -SCN, -NO, -NO_ {2}, = N_ {{}}, -N_ {3}, -S (O) R f, -S (O) 2 R f, -S (O) 2 OR f, -S (O) NR f R f, -S (O) 2 NR f R f, -OS (O) R f, -OS (O) 2 R f, -OS (O) 2 OR f, -OS (O) 2 NR f R f, -C (O) R f, -C (O) OR f, -C (O) NR f R f, -CN (R g) NR f R f, -OC (O) R f, -OC (O) OR f, -OC (O) NR f R f, -OCN (R g) NR f R f, -N (R g) C (O) R f, -N (R g) C (S) R f, -N (R g) S (O) 2 R c, -N (R g) C (O) OR f, -N (R g) C (O) NR f R f and -N (R g) CN (R g) NR f R f;

quad

each R f, independently of each other, is hydrogen or a radical optionally substituted with one or more R g the same or different, chosen from the group consisting of alkyl C 1-6, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, aryl C 6-10, C 7-16 arylalkyl, 2-6 membered heteroalkyl, heterocycloalkyl of  3-8 members, 4-14 heterocycloalkyl-alkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

quad

each R g, independently of each other, is hydrogen, C 1-6 alkyl, cycloalkyl C 3-8, cycloalkylalkyl C 4-11, aryl C 6-10, C 7-16 arylalkyl, heteroalkyl of 2-6 members, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkylalkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

which can be in the form of their tautomers, of their racemates, of their enantiomers, of their diastereoisomers and their mixtures, as well as, where appropriate, their pharmacologically safe addition salts.

       \ vskip1.000000 \ baselineskip
    

An aspect of the present invention are compounds of the general formula (1) in which R 3 means a radical chosen from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, optionally substituted with one or more R 4.

Another aspect of the present invention are compounds of the general formula (1) in which R 3 means pyridyl

Another aspect of the present invention are compounds of the general formula (1) in which R 1 means -NHC (O) R c.

Another aspect of the present invention are compounds of the general formula (1) in which R 1 means -NHC (O) CH 3.

An aspect of the present invention are compounds of the formula (A)

3

where

quad

X means -CH 3, -OR 4 or -SR 4 Y

quad

And phenyl, 5-10 heteroaryl members or the group -C (O) O and

quad

R y hydrogen, -NO 2 or alkyl C 1-6 and R 4 is defined as previously.

       \ vskip1.000000 \ baselineskip
    

Another aspect of the present invention are compounds of the general formula (A) in which R 4 means C 1-6 alkyl.

Another aspect of the present invention is the use of compounds of the formula (A) as synthesis intermediates.

An aspect of the present invention are compounds of the general formula (1) or their pharmaceutically salts Useful as medications.

An aspect of the present invention is the use of compounds of the general formula (1) or their salts pharmaceutically useful, to make an action medication antiproliferative

An aspect of the present invention is a Pharmaceutical preparation containing as active ingredient one or various compounds of the general formula (1) or their salts physiologically compatible and, if necessary, in combination with auxiliary substances and / or current support.

Another aspect of the present invention is the use of compounds of the general formula (1) to prepare a medicine intended for the treatment and / or prevention of cancer.

An aspect of the present invention is a Pharmaceutical preparation comprising a compound of the formula general (1) and at least one other cytostatic active substance or cytotoxic different from formula (1), possibly in the form of their tautomers, of their racemates, of their enantiomers, of their diastereoisomers and their mixtures, as well as, where appropriate, their pharmacologically safe addition salts.

Definitions

As used here, the following are worth definitions, unless otherwise described.

As alkyl substituents are understood saturated aliphatic hydrocarbon radicals (alkyl radicals), unsaturated, linear or branched, respectively, and include both saturated alkyl radicals and unsaturated radicals alkenyl and alkynyl. Alkenyl substituents are radicals unsaturated, branched or linear alkyl respectively, which They have at least one double bond. As alkynyl substituents are they understand unsaturated, branched or linear alkyl radicals respectively, which have at least one triple bond.

Heteroalkyl represents hydrocarbon chains aliphatic, linear or branched, interrupted by one to three heteroatoms, in which each of the carbon atoms and of nitrogen present in the heteroalkyl chain may be respectively substituted, independently of each other, and heteroatoms are chosen respectively, independently of each other, of the group consisting of O, N and S (e.g. dimethyl aminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethyl aminomethyl, diethylaminoethyl, diethylaminopropyl, 2-diiso-propylaminoethyl, bis-2-methoxyethylamino, [2- (dimethylamino-ethyl) -ethyl-amino] -methyl, 3- [2- (dimethylamino-ethyl) -ethyl-amino] -propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl).

Halogenalkyl refers to alkyl radicals, in which one or more hydrogen atoms are replaced by halogen atoms Haloalkyl comprises both radicals saturated alkyl as unsaturated alkenyl and alkynyl radicals, for example -CF_ {3}, -CHF_ {2}, -CH_ {2}, -CF_ {2} CF_ {3}, -CHFCF 3, -CH 2 CF 3, -CF 2 CH 3, -CHFCH 3, -CF 2 CF 2 CF 3, -CF 2 CH 2 CH 3, -CF = CF 2, -CCl = CH2, -CBr = CH2, -CI = CH2, -C \ equivC-CF_ {3}, -CHFCH_ {2} CH_ {3} and -CHFCH_ {2} CF_ {3}.

Halogen refers to fluorine atoms, chlorine, bromine and / or iodine.

A cycloalkyl is a ring monocyclic or bicyclic, whose rings can be saturated or non-aromatic unsaturated, such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl and norbornenyl.

Cycloalkylalkyl includes a non-alkyl group cyclic, in which a hydrogen atom attached to an atom of Carbon - normally a C-terminal atom - is replaced by a cycloalkyl group.

Aryl refers to monocyclic rings or bicyclics of 6-12 carbon atoms, as per example phenyl and naphthyl.

Arylalkyl includes a non-cyclic alkyl group, in which a hydrogen atom attached to a carbon atom -Normally a terminal C atom- is substituted by a group aryl

As heteroaryl, monocyclic or bicyclic rings are understood which instead of one or more carbon atoms carry one or more same or different heteroatoms, such as p. ex. nitrogen, sulfur or oxygen atoms. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, iso-xazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heteroaryl radicals include indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahidrofurilo, isobenzotetrahydrothienyl, isobenzothienyl, pyridopyridyl, benzotetrahidrofurilo, benzotetrahidrotienilo, purinyl, benzodioxolyl, triazinyl, fenoxiazinilo, fenoxitiazinilo, pteridinyl, imidazothiazolyl, dihidrobenzisoxazinilo, benzisoxazinilo, benzoxazinyl, dihidrobenzisotiazinilo, benzopyranyl, benzothiopyranyl, coumarinyl, isocumarinyl, chromonyl, chromanonyl, pyridyl- N- oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocumarinyl, dihydroisocumarinyl or, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrolyl- N -oxide, pyrimidinyl- N -oxide, pyridazinyl- N -oxide, pyrazinyl- N -oxide, quinolinyl- N -oxide, indolyl- N -oxide, indolinyl- N -oxide, isoquinolyl- N -oxide, quinazolinyl- N -oxide, quinoxalinyl- N -oxide, phthalazinyl- N -oxide, imidazolyl- N -oxide, isoxazolyl- N -oxide, oxazolyl- N -oxide, thiazolyl- N -oxide, indolizinyl- N -oxide, indazolyl- N -oxide, benzothiazolyl- N -oxide, benzimi-
dazolyl- N -oxide, pyrrolyl- N -oxide, oxadiazolyl- N -oxide, thiadiazolyl- N -oxide, triazolyl- N -oxide, tetrazolyl- N -oxide, ben-
Zothiopyranyl- S -oxide and benzothiopyranyl- S, S -oxide.

Heteroarylalkyl comprises a non-alkyl group cyclic in which a hydrogen atom attached to an atom of Carbon - normally a C-terminal atom - is replaced by a heteroaryl group.

Heterocycloalkyl refers to non-aromatic, saturated or unsaturated rings of 3-12 carbon atoms, including monocyclic, bicyclic or bridged bicyclics, which instead of one or more carbon atoms carry heteroatoms such as nitrogen, oxygen or sulfur. Examples of such heterocycloalkyl radicals include tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, tiomorfolinil- S -oxide, tiomorfolinil- S, S -oxide, tetrahydropyranyl, tetrahydrothienyl, homotiomorfolinil- S, S -oxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahidrotienil- S -oxide, tetrahidrotienil- S, S -oxide, homotiomorfolinil- S -oxide, 2-oxa-5-aza-bicyclo- [2.2.1] heptane, 8-oxa-3-aza-bicyclo [3.2.1] octane, 3,8-diaza-bicyclo [3.2.1] octane , 2,5-diaza-bicyclo [2.2.1] heptane, 3,9-diaza-bicyclo [4.2.1] nonano and 2,6-diaza-bicyclo [3.2.3] nonano.

Heterocycloalkylalkyl refers to a group non-cyclic alkyl in which a hydrogen atom attached to an atom carbon - usually a C-terminal atom - is substituted by a heterocycloalkyl group.

The following examples illustrate the present invention, but without limiting its scope.

Reagent Synthesis R-1) cis -1-methylamino-4- (pyrrolidin-1-yl) -cyclohexane

       \ vskip1.000000 \ baselineskip
    

4

R-1a) cis- 4- (pyrrolidin-1-yl) -cyclobuthexancarbamate tert -butyl

5

A solution of cis- 4-aminocyclohexancarbamate of tert - butyl (10 g, 46 mmol) and 1,4-dibromobutane (12.1 g, 56 mmol) in 400 ml of DMF is mixed with 25 g of potassium bicarbonate and stirred for 24 hours TA. Then the reaction mixture is concentrated, diluted in diethyl ether and washed with water. The organic phase is dried and concentrated in vacuo. Yield: 12 g.

R-1b) tert -butyl N- methyl- cis -4- (pyrrolidin-1-yl) -cyclohexan-carbamate

6

R-1a (5 g, 18 mmol) is dissolved in 20 ml of N, N- dimethylacetamide and added to a suspension of sodium hydride (60% in paraffin oil, 0.8 g, 20 mmol) in 20 ml of N, N- dimethylacetamide at 37 ° C, so that the temperature does not rise above 48 ° C. At the end of the foaming, methyl iodide (2.9 g, 20 mmol) is added and stirred 10 min. to TA. The reaction mixture is mixed with ethyl acetate and washed with water. The organic phase is then mixed with oxalic acid and washed with ethyl acetate. It is then basified with potassium bicarbonate and extracted with ethyl acetate. The organic phases are concentrated and used in the reaction without any additional purification step. Yield: 1.4 g.

R-1b dissolves (1.4 g, 5 mmol) in 50 ml of dichloromethane, mixed with 25 ml of acid trifluoroacetic and stir 4 h at RT. After concentrating the reaction mixture, the desired product precipitates as dihydrochloride with hydrochloric acid (1 N in diethyl ether). Yield: 1 g.

R-2) trans-1-amino-4- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -cyclohexane

7

To a solution of 2,5-bis (p-tosyloxymethyl) tetrahydro-furan (44 g, 0.1 mol) in 440 ml of toluene is added successively triethylamine (21 g, 0.21 mol), trans -4-amino benzyl cyclohexyl carbamate (24.8 g, 0.1 mol), as well as a catalytic amount of DMAP. The reaction mixture is heated at reflux for 6 days. After cooling, the organic phase is decanted from the insoluble resin and the residue is purified by chromatography. The resulting intermediate product is suspended in 300 ml of methanol and mixed with 37 ml of hydrochloric acid (6 N in isopropanol) and with 6 g of palladium on activated carbon, in the autoclave. The reaction mixture is stirred 15 h at RT under hydrogen atmosphere (50 bar). The filtrate is concentrated after filtering over Celite®, dissolved in hot ethyl acetate and mixed with 37 ml of hydrochloric acid (6 N in isopropanol). Upon cooling, the desired product precipitates as a hydrochloride salt, which is filtered and dried.

R-3) 1-amino-4- (methylpropylamino) cyclohexane

8

R-3a) cis -4- (2,2,2-trifluoroacetylamino) -tert- butyl cyclohexanecarbamate

       \ vskip1.000000 \ baselineskip
    

9

A solution of cis- 4-aminocyclohexanecarbamate of tert - butyl (22.1 g, 103 mmol) and methyl trifluoroacetate (11 ml, 110 mmol) in 110 ml of methanol is stirred 4 h at RT. After cooling the reaction mixture to 0 ° C a precipitate is obtained, which is filtered, washed with diethyl ether and dried. Yield: 17.6 g.

       \ vskip1.000000 \ baselineskip
    

R-3b) tert -butyl cis- 4-methyl- (2,2,2-trifluoroacetyl) amino) -cyclohexane-carbamate

       \ vskip1.000000 \ baselineskip
    

10

A suspension of R-3a) (8.3 g, 27 mmol) in 100 ml of N, N- dimethylacetamide is mixed at RT under a nitrogen atmosphere with sodium hydride (60% in paraffin oil, 1.3 g, 32 mmol). After 20 min. Methyl iodide (4.5 g, 32 mmol) is added and stirred at RT for 15 h. After hydrolyzing with 800 ml of ice water, the precipitate is filtered and washed with water and then with petroleum ether. The residue is mixed with 200 ml of diisopropylether and recrystallized with 10 ml of acetonitrile. Yield: 11 g.

       \ vskip1.000000 \ baselineskip
    

R-3c) tert - butyl cis- 4-methylamino-cyclohexanecarbamate

       \ vskip1.000000 \ baselineskip
    

eleven

To separate the trifluoroacetate group, mix R-3b (39.7 g, 123 mmol) with 117 ml of hydroxide sodium (2 N) in 536 ml of methanol and stir 5 h at RT. Mix Reactant is concentrated and stirred with water and ethyl acetate. The Organic phase is dried, filtered and concentrated in vacuo. Yield: 28.4g.

       \ vskip1.000000 \ baselineskip
    

R-3d) cis -4- (methylpropylamino) -t- butyl cyclohexanecarbamate

       \ vskip1.000000 \ baselineskip
    

12

To a solution of R-3c (2 g, 8.8 mmol) in 5 ml of acetonitrile is added triethylamine (0.98 g, 9.7 mmol) and n -propyl bromide (1.2 g, 9, 7 mmol) and stir 3 h in the pressure tube at 60 ° C. Then the reaction mixture is concentrated and extracted with water and ethyl acetate. Yield: 1 g.

The separation of the BOC protecting group has place analogously to obtaining R-1, by using R-3d (1 g, 3.7 mmol), 20 ml of trifluoroacetic acid and 20 ml of dichloromethane. Yield: 0.6 g.

R-4) cyclopropyl-piperidin-4-yl-amine

13

A solution of 1- tert -butoxycarbonyl-piperidin-4-one (1 g, 5 mmol) and cyclopropylamine (352 µl) in 15 ml of 1,2-dichloroethane is stirred 20 min. at RT and then mixed with sodium triacetoxyborohydride (1.6 g, 7 mmol) and 0.3 ml of acetic acid. After stirring for 15 h at RT, the reaction mixture is hydrolyzed with saturated sodium bicarbonate solution and extracted with 2 x 50 ml of dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried, filtered and concentrated. The residue is dissolved in 4 ml of diethyl ether and mixed with 8 ml of hydrochloric acid (4 N in dioxane). After stirring for 15 h at RT, the precipitate is filtered and washed with diethyl ether. The desired product is obtained as hydrochloride. Yield: 0.96 g.

       \ vskip1.000000 \ baselineskip
    

R-5) 1-Cyclopentyl-piperidin-4-carboxylic acid

14

To a solution of ethyl piperidine-4-carboxylate (22.9 g, 145 mmol) and cyclopentanone (13.5 g, 160 mmol) in 400 ml of THF are added catalytic amounts of p- toluenesulfonic acid (750 mg) and 12.5 ml of glacial acetic acid. After stirring 30 min. at RT sodium triacetoxyborohydride (42 g, 190 mmol) is added in portions. The reaction mixture is stirred for 15 h at RT and after concentrating it is extracted with sodium carbonate solution and dichloromethane. The organic phase is dried, filtered and concentrated. Yield: 32 g of ethyl 1-cyclopentylpiperidine-4-carboxylate. The intermediate compound (1 g, 4.4 mmol) is then saponified with 10 ml of NaOH (5 N) in 10 ml of EtOH for 15 h at 80 ° C. The reaction mixture is acidified after cooling and the resulting precipitate is filtered.

       \ vskip1.000000 \ baselineskip
    

R-6) cis -4- (pyrrolidin-1-yl) cyclohexanecarboxylic acid

fifteen

A solution of cis- 4-aminocyclohexane-carboxylate hydrochloride (4 g, 21 mmol) in 32 ml of DMF is mixed with 1,4-dichlorobutane (2.3 ml, 21 mmol), potassium carbonate (12.6 g, 91 mmol) and potassium iodide (400 mg) 6 h at 100 ° C and then stirred for 3 days at RT. The reaction mixture is diluted with 200 ml of water, neutralized with glacial acetic acid, saturated with sodium chloride and extracted with dichloromethane. The organic phases are dried, filtered and concentrated. Yield: 3.8 g of methyl cis -4- (pyrrolidin-1-yl) -cyclohexanecarboxylate. The intermediate product is then stirred 15 h at RT in 10 ml of methanol with 25 ml of sodium hydroxide (1 N). After removing methanol in vacuo, the reaction mixture is adjusted to pH 6 with hydrochloric acid and the concentration is continued. The residue is dissolved in methanol and purified by filtration on silica gel. Yield: 3.5 g.

       \ vskip1.000000 \ baselineskip
    

R-7) 3-morpholin-4-yl-cyclobutylamine

16

R-7a) 3- tert -butoxycarbonylamino-cyclobutyl toluene-4-sulfonate

17

To a solution of 3- tert -butoxycarbonylaminocyclobutanol (18.7 g, 0.1 mol) and triethylamine (12.1 g, 0.12 mol) in 500 ml of chloroform, a chloride solution is added dropwise at 0 ° C of toluene-4-sulfonic acid (20.5 g, 0.105 mol) in 150 ml of chloroform and then heated to RT. The organic phase is washed successively with water, dilute hydrochloric acid, sodium bicarbonate solution and again with water, before drying, filtering and concentrating.

       \ vskip1.000000 \ baselineskip
    

R-7b) 1-morpholin-1-yl-3- tert -butoxycarbonylamino-cyclobutane

18

R-7a dissolves (34 g, 0.1 moles) in 750 ml of morpholine, mixed with a catalytic amount DMAP and stir 3 h at 100 ° C under argon. TO then the reaction mixture is concentrated in vacuo, it is evaporate together with 100 ml of toluene and dissolve in 500 ml of ethyl acetate. The organic phase is washed with saturated solution of sodium bicarbonate, dried, filtered and concentrated, so which the desired compound is obtained, which is used without purification plus. R-7b (25.6 g, 0.1 mol) is mixed with 260 ml of hydrochloric acid (2 N) and stir 2 h at 40 ° C. One time After completion of the reaction, the reaction mixture is made alkaline with methanolic ammonia solution, filtered and concentrated. He residue is then recrystallized from a solution in ethanol, obtaining R-7.

       \ vskip1.000000 \ baselineskip
    

H-1) methyl 4-hydrazino-3-methyl-benzoate

19

It mixes 4-amino-3-methyl benzoate of methyl (10 g, 61 mmol) with 50 ml of hydrochloric acid concentrated and cooled to -15 ° C. A solution is added dropwise of sodium nitrite (6.3 g, 91 mmol) in 50 ml of water, so the temperature does not exceed -5ºC. After 4 h of stirring at -10 ° C add a solution of chloride of drop by drop to the suspension tin (II) dihydrate in 50 ml of hydrochloric acid concentrated, without the reaction temperature rising above -5 ° C. The thick suspension is stirred 15 h at RT, before adjust it to pH 14 with 200 ml of sodium hydroxide (10 N). Mix reactant is filtered through diatomaceous earth and Extrelut® (60 g) and wash with 2 l of chloroform. The resulting organic phase wash with water (2 x 200 ml), dry over sodium sulfate and dry Concentrate in vacuo. The residue is stirred with 120 ml of ether of oil and seeps. Yield: 6.3 g.

       \ vskip1.000000 \ baselineskip
    

H-2) methyl 4-hydrazino-3-fluoro-benzoate

twenty

In a manner analogous to the preparation of H-1, starting from 4-amino-3-fluoro-benzoate methyl (3.9 g, 23 mmol), sodium nitrite (2.4 g, 34 mmol) and tin (II) chloride dihydrate (20.8 g, 92 mmol), is Get the desired compound. Yield: 3.4 g.

H-3) 3-iodo-phenylhydrazine

twenty-one

In a manner analogous to the preparation of H-1, starting from 3-iodoaniline (2.75 g, 22.8 mmol), sodium nitrite (1.58 g, 22.8 mmol) and tin (II) chloride dihydrate (15.4 g, 68.5 mmol), se Obtain the desired compound in the form of hydrochloride. Performance: 3.55 g

       \ vskip1.000000 \ baselineskip
    

H-4) 3-hydrazino-phenylacetic acid

22

In a manner analogous to the preparation of H-1, starting from acid 3-aminophenylacetic (2 g, 13.2 mmol), nitrite sodium (0.91 g, 13.2 mmol) and tin (II) chloride dihydrate (6.1 g, 26.4 mmol), the desired compound is obtained.

       \ vskip1.000000 \ baselineskip
    

H-5) piperidin-3-yl-hydrazine

2. 3

Under argon, 4-oxo-piperidin-1- tert- butoxycarbonyl (500 mg, 2.5 mmol) is dissolved in hexane and mixed with tert- butylcarbazate (332 mg, 2.5 mmol). After heating 20 min. at reflux, the reaction mixture is cooled and the precipitate obtained is filtered. 4- ( tert -butoxycarbonylhydrazono) -piperidin-1- tert -butoxycarbonyl (707 mg, 2.3 mmol) is mixed with borane-THF complex (1 M in THF; 2.2 ml) and stirred 1 h at RT . The desired product is then precipitated in the form of hydrochloride with 6 ml of hydrochloric acid (4 N in dioxane) and filtered.

       \ vskip1.000000 \ baselineskip
    

H-6) ethyl 4-hydrazino-cyclohexanecarboxylate

24

Similarly to the preparation of H-5, starting from ethyl 4-oxo-cyclohexanecarboxylate (4.5 g, 26.4 mmol), tert -butylcarbazate (3.5 g, 26.4 mmol) and borane complex- THF (1 M in THF; 26.5 ml), the desired compound is obtained in the form of a cis / trans mixture, which is used without further purification or is separated by chromatography on silica gel, with 0-33% acetate ethyl in cyclohexane.

Performance: cis : 2.2 g trans : 2.6 g

H-7) 2-Chloro-4-hydroxymethylphenylhydrazine

25

At a dissolution of 3-chloro-4-hydrazino-benzoate of methyl (9.5 g, 47 mmol) in 1 l of toluene is added dropwise to drop at -73 ° C under nitrogen hydride atmosphere of diisobutyl aluminum (1 M in toluene, 190 ml), of so that the temperature does not exceed -70 ° C. The reaction mixture is stir 30 minutes at -73 ° C and then heat to -5 ° C. After hydrolyze with 500 ml of water, the precipitate is filtered and washed with ethyl acetate (5 x 500 ml). The organic phase is concentrated, the residue dissolves in some ethyl acetate, precipitates with petroleum ether / diethyl ether and filtered. The resulting solid is Purify by chromatography on silica gel, with cyclohexane / ethyl acetate. Yield: 2.9 g.

       \ vskip1.000000 \ baselineskip
    

H-8) methyl 3-hydrazinomethylbenzoate

26

A solution of 3 g of methyl 3-bromomethylbenzoate (13 mmol), 2.6 g of tert -butoxycarbonylhydrazine (19 mmol) and 3.1 g of potassium carbonate (23 mmol) in 30 ml of DMF is stirred 24 h at RT . After adding water, the reaction mixture is extracted with dichloromethane. The organic phase is dried, filtered and concentrated, and the residue is purified by chromatography. The BOC protecting group is then separated with 30 ml of hydrochloric acid (4 M in dioxane). Yield: 1.25 g.

       \ vskip1.000000 \ baselineskip
    

H-9) (4-Trifluoromethyl-pyridin-3-yl) -hydrazine

27

In a manner analogous to the preparation of H-1, starting from 3-amino-4-trifluoromethylpyridine (5.1 g, 31 mmol), sodium nitrite (2.2 g, 31 mmol) and chloride tin (II) dihydrate (21.6 g, 94 mmol), the desired compound. Yield: 3.8 g.

       \ vskip1.000000 \ baselineskip
    

H-10) N - (4-hydrazinophenyl) - N -methyl-acetamide

28

Similarly to the preparation of H-1, starting from N - (4-aminophenyl) - N -methyl-acetamide (0.4 g, 2.4 mmol), of sodium nitrite (0.2 g, 2.7 mmol) and tin (II) chloride dihydrate (1.6 g, 7.3 mmol), the desired compound. Yield: 0.2 g.

H-11) (4-morpholin-4-ylmethyl-phenyl) -hydrazine

29

In a manner analogous to the preparation of H-1, starting from 4-morpholin-4-ylmethyl-phenylamine (1.1 g, 5 mmol), sodium nitrite (0.3 g, 5 mmol) and chloride tin (II) dihydrate (5.8 g, 25 mmol), the desired compound. Yield: 0.3 g.

       \ vskip1.000000 \ baselineskip
    

H-12) pyrrolidin-3-yl-hydrazine

30

Similarly to the preparation of H-5, starting from tert - butyl 3-oxo-pyrrolidin-1-carboxylate, the desired compound is obtained in the form of hydrochloride.

       \ vskip1.000000 \ baselineskip
    

H-13) [3- (2-methylpropan-1-sulfonyl) -phenyl] -hydrazine

31

Similarly to the preparation of H-1, starting from 3- (2-methylpropan-1-sulfonyl) -phenylamine (1.5 g, 7 mmol), which can be obtained in a similar way to the literature (A. Courtin , Helv. Chim. Acta 1981 , 64, 1849), from sodium nitrite (0.5 g, 7 mmol) and tin (II) chloride dihydrate (4.9 g, 21 mmol) the desired compound is obtained as hydrochloride Yield: 1.8 g.

       \ vskip1.000000 \ baselineskip
    

H-14) 4-Hydrazinophenylacetonitrile

32

In a manner analogous to the preparation of H-1, starting from 4-aminophenylacetonitrile (5 g, 37.8 mmol), nitrite sodium (2.6 g, 37.4 mmol) and tin (II) chloride dihydrate (25.8 g, 112 mmol), the desired compound is obtained in the form of hydrochloride Yield: 5.4 g.

       \ vskip1.000000 \ baselineskip
    

H-15) (1-methyl-1 H -indazol-5-yl) -hydrazine

33

Similarly to the preparation of H-1, starting from 1-methyl-1 H -indazol-5-ylamine (0.9 g, 6 mmol), sodium nitrite (0.44 g, 6.4 mmol) and chloride from tin (II) dihydrate (2.8 g, 12.6 mmol) the desired compound is obtained in the form of hydrochloride. Yield: 1.2 g.

       \ vskip1.000000 \ baselineskip
    

Synthesis of intermediate compounds Z-1) N - [7-oxo-6- (pyrimidin-5-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] -acetamide

3. 4

A solution of 10 g (48 mmol) of Z-6 in 1 L of THF is cooled to -40 ° C and mixed drop by drop with 143 ml (143 mmol) of Li-HMDS (1 N in THF) so that the temperature does not exceed -20ºC. After 3.5 h between -40ºC and -20ºC, hydrochloride of pyrimidin-5-carbonyl chloride (10.2 g, 57 mmol) and stir 16 h at RT. Then they are added 200 ml of hydrochloric acid (1 N in Et2O) to the mixture transparent reactant and a precipitate forms. The suspension mix with 300 ml of phosphate buffer and once separated the Organic phase is extracted with ethyl acetate. Organic phases together they are dried over magnesium sulfate and evaporated until dryness. The residue is crystallized from solution of acetonitrile Yield: 13.2 g. The crude product is used in other syntheses, without purifying it further.

       \ vskip1.000000 \ baselineskip
    

Z-3) N - [7-oxo-6- (pyrazin-2-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] -acetamide

35

To a suspension of 8.1 g (143 mmol) of Sodium methylate in 100 ml of DMF is added 10 g (48 mmol) of Z-6 in portions, so that the temperature does not exceed 30 ° C. After stirring for 1 h at RT the mixture reactant is heated to 55 ° C and combined with a solution of 10 g (72 mmol) of methylpyrazin-2-carboxylate in 40 ml Benzene The solution is stirred 3 h at 55 ° C and 15 h at RT, before adjust it to pH 3 with hydrochloric acid (4 N in dioxane). After hydrolyze with phosphate buffer, the reaction mixture is extracted with ethyl acetate. The combined organic phases are dried and dried. concentrate in vacuo. The residue is recrystallized from solution of ether / petroleum ether. Yield: 8.7 g.

       \ vskip1.000000 \ baselineskip
    

Z-4) N - [6- (3-nitrobenzoyl) -7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl] -acetamide

36

Similarly to the preparation of the compound intermediate Z-1, starting from 2.5 g (12 mmol) of Z-6, 4.2 g (22 mmol) of 3-nitrobenzoylchloride and 36 ml (36 mmol) of Li-HMDS (1 N in THF), 5.2 g of Z-4 The crude product is used in other syntheses, without purify it more.

       \ vskip1.000000 \ baselineskip
    

Z-5) N - [6- (4-nitrobenzoyl) -7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl] -acetamide

37

Similarly to the preparation of the compound intermediate Z-1, starting from 1 g (4.8 mmol) of Z-6, 1.2 g (6.2 mmol) of 4-nitrobenzoylchloride and 14.6 ml (14.6 mmol) of Li-HMDS (1 N in THF), 2.2 g of Z-5 The crude product is used in other syntheses, without purifying it further.

Z-6) N - (7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl) -acetamide

       \ vskip1.000000 \ baselineskip
    

38

       \ vskip1.000000 \ baselineskip
    

to)

Be suspend 112 g (1 mol) of 1,3-cyclohexanedione in 700 ml of ice water and for 45 min. 51.6 are added dropwise ml (1 mol) of bromine at 0 ° C. The suspension continues to stir 3.5 h at 10ºC maximum. Then it is filtered by aspirating and the solid melts in 800 ml of water, it is aspirated again, washed with 3 l of water and dry The resulting solid is recrystallized from solution Etanolic Yield: 37 g (Z-6a).

b)

Be prepare 15.5 g (0.2 mol) of thiourea in 200 ml of ethanol at room temperature. To this suspension are added 37.1 g (0.2 moles) of Z-6a in portions and then washed with 60 ml of ethanol The slowly formed solution is stirred for 2 h at reflux. and then it is concentrated by evaporation. The residue is extracted with water and diethyl ether and the aqueous phase is basified with solution of sodium carbonate. The solid formed is filtered by aspiration, it is wash with water, then melt with methanol and evaporate until dryness. Yield: 22 g (Z-6b).

C)

be prepare 230 ml (2.4 mol) of acetic anhydride at temperature ambient, 22 g (0.13 mol) of Z-6b are added and stir 3 h at reflux, whereby the suspension dissolves partially. After cooling in a common ice / salt bath, the solid is filtered by aspirating, boiled twice in 150 ml of Acetone, it is aspirated and dried. Yield: 25 g (melting point: 268-272 ° C).

       \ vskip1.000000 \ baselineskip
    

Z-7) N - (6-formyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl) -acetamide

       \ vskip1.000000 \ baselineskip
    

39

       \ vskip1.000000 \ baselineskip
    

20 g (0.37 mol) of methylate are suspended sodium in 50 ml of dimethylformamide and a drop is added dropwise 21 g suspension (0.1 mol) of Z-6 in 100 ml of DMF Stirring is continued 15 min. and then cooled to 0 ° C. It adds drop by drop a mixture of 29.9 ml (0.37 mol) of ethyl formate and 60 ml of benzene and the reaction mixture is diluted with 100 ml More Benzene Gradually a precipitate forms and continues stirring 3.5 h at 0 ° C. The suspension is hydrolyzed with 370 ml of 1 molar hydrochloric acid and the precipitated solid is filtered aspiring. The two phases of the mother liquor are separated, the phase Aqueous is extracted with dichloromethane. The resulting organic phase is Dry and evaporate to dryness. The solid and the residue of the extraction are recrystallized from a solution in acetonitrile Yield: 20 g.

       \ vskip1.000000 \ baselineskip
    

Z-8) N - [6- (furan-2-carbonyl) -7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl] -acetamide

       \ vskip1.000000 \ baselineskip
    

40

       \ vskip1.000000 \ baselineskip
    

Similarly to the preparation of Z-7, starting from 2 g (10 mmol) of Z-6, 1.6 g (30 mmol) of sodium methylate and 3.8 g (30 mmol) of methyl 2-furancarboxylate, se they get 1.7 g of Z-8. (Fusion point: 255-256 ° C).

Z-10) (2-Acetylamino-7-oxo-4,5,6,7-tetrahydro-benzothiazol-6-yl) -oxo-methyl acetate

41

Similarly to the preparation of Z-7, starting from 40 g (190 mmol) of Z-6, 38 g (0.7 mol) of sodium methylate and 84 g (0.7 mol) of dimethyloxalate, 52 g of Z-10

       \ vskip1.000000 \ baselineskip
    

Z-11) N - (6-benzoyl-7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl) -acetamide

42

Similarly to the preparation of Z-7, starting from 10 g (50 mmol) of the product intermediate 1, 7.8 g (140 mmol) of sodium methylate and 17.9 ml (140 mmol) of methyl benzoate, 3.6 g of Z-11

       \ vskip1.000000 \ baselineskip
    

Z-12) N - [7-oxo-6- (pyridin-3-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] -acetamide

43

Similarly to the preparation of Z-7, starting from 4 g (19 mmol) of Z-6, 3.9 g (57 mmol) of sodium methylate and 7.9 g (57 mmol) of methyl nicotinate, 3.1 g of product are obtained Z-12

       \ vskip1.000000 \ baselineskip
    

Z-13) [7-Oxo-6- (pyridin-3-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] -methylcarbamate

44

to)

2-Amino-5,6-dihydro-4 H -benzothiazol-7-one. A suspension of 23 g of Z-6 (109 mmol) in a mixture of 300 ml of hydrochloric acid (4 M in dioxane) and 30 ml of water is stirred 15 h at 60 ° C. After cooling to 0 ° C, the reaction mixture is made alkaline with 8 N sodium hydroxide (pH 10). The precipitate is filtered, washed with diethyl ether and used without further purification. Yield: 22.4g.

b)

Methyl (7-Oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl) -carbamate. To a solution of 500 mg of 2-amino-5,6-dihydro-4 H -benzothiazol-7-one (2.4 millimoles) in 5 ml of pyridine is added 572 µl of methyl chloroformate (7.3 mmoles). The reaction mixture is stirred for 15 h at 50 ° C, then diluted with ethyl acetate, extracted twice respectively with water and with cold 1 N hydrochloric acid. The organic phase is dried and concentrated. Yield: 290 mg.

C)

From analogous to the preparation of Z-1, starting from 340 mg of (7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl) -carbamate of methyl (1.5 mmol), 4.7 ml of Li-HMDS (1 N in THF) and 520 mg of imidazol-1-yl-pyridin-3-yl-methanone (3 mmol) in 30 ml of THF, the desired compound is obtained. Yield: 480 mg.

Z-14) [7-Oxo-6- (pyridin-3-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] -thiocarbamate ethyl

Four. Five

to)

(7-Oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl) -thiocarba-ethyl matte. Similarly to the preparation of Z-13b, starting from 101 g of 2-amino-5,6-dihydro-4 H -benzothiazol-7-one (602 mmol) in 3.4 l of pyridine and 75 g of chlorothioformate ethyl (602 mmol) the desired thiocarbamate is obtained. Yield: 84 g.

b)

From analogous to the preparation of Z-1, starting from 17 g of (7-Oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl) -thiocarbamate ethyl (67 mmol), 200 ml Li-HMDS (1 N in THF) and 23 g of imidazol-1-il-piri-din-3-il-methanone (133 mmol) in 400 ml of THF, the desired compound is obtained. Yield: 18 g.

       \ vskip1.000000 \ baselineskip
    

Z-15) [7-Oxo-6- (pyrimidin-5-carbonyl) -4,5,6,7-tetrahydro-benzothiazol-2-yl] -thiocarbamate ethyl

46

Similarly to the preparation of Z-1, starting from 12 g of (7-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl) -thiocarbamate ethyl (Z-14a, 46 mmol), 140 ml of Li-HMDS (1 N in THF) and 12 g of imidazol-1-yl-pyrimidin-5-yl-methanone (56 mmol) in 300 ml of THF, the desired compound results. Yield: 13 g.

       \ vskip1.000000 \ baselineskip
    

I-1) 4- (7-Acetylamino-4,5-dihydro-pyrazolo [3 ', 4': 3,4] -benzo [1,2- d ] thiazol-1-yl) -3-chlorobenzoic acid

47

A suspension of Z-13 (480 mg, 1.5 mmol) and 2-chlorophenylhydrazine hydrochloride (267 mg, 1.5 mmol) in 10 ml of glacial acetic acid is stirred 4 h at 100 ° C. The reaction mixture is then diluted with 500 ml. of water and the precipitate is filtered off. Yield: 116 mg

       \ vskip1.000000 \ baselineskip
    

I-3) N - [1- (2-Chloro-pyridin-4-yl) -3-furan-2-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] -benzo [1,2- d ] thiazol-7-yl] -acetamide

48

Similarly to the preparation of I-1, starting from Z-8 (1.5 g, 5 mmoles) and hydrochloride 2-chloropyridin-4-yl-hydrazine in 25 ml of glacial acetic acid, the desired product is obtained. Yield: 1.6 g.

I-4) 4- (7-Acetylamino-3-furan-2-yl-4,5-dihydro-pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1- acid il) -3-chlorobenzoic

49

Similarly to the preparation of I-1, starting from Z-8 (12 g, 35 mmoles) and of 3-chloro-4-hydrazinobenzoate of methyl (8.5 g, 35 mmol) in 80 ml of glacial acetic acid stir 4 days at RT. The methyl ester (1.1 g) obtained by precipitating in ice water it is then saponified with lithium hydroxide (178 mg in 15 ml of dioxane). Acidifying with 2 N hydrochloric acid the desired product is solid. Yield: 0.8 g.

       \ vskip1.000000 \ baselineskip
    

I-6) 7-Acetylamino-1-phenyl-4,5-dihydro-1 H -pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-3-carboxylic acid

fifty

Similarly to the preparation of I-1, starting from 30 g (0.1 mol) of Z-10 and 10.3 ml (0.1 mol) of phenylhydrazine are obtain 27 g of product (melting point: 298-300 ° C). 0.1 g (0.3 mmol) are suspended from this in 12 ml of methanol / water (1: 1) and mixed with 0.4 ml of solution of 10% potassium hydroxide. After 1.5 h the concentration is concentrated. reaction mixture and the solution is acidified with hydrochloric acid diluted. The resulting precipitate is recrystallized from a solution. in acetonitrile. Yield: 0.1 g (melting point:> 300 ° C).

       \ vskip1.000000 \ baselineskip
    

I-8) 4- (7-acetylamino-3-phenyl-4,5-dihydro-pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1-yl) -3- chlorobenzonitrile

51

Similarly to the preparation of I-1, starting from Z-11 (10 g, 12.7 mmoles) and 3-chloro-4-hydrazinobenzonitrile (4.5 g, 26.8 mmol) in 50 ml of glacial acetic acid, is obtained The desired product. Yield: 1.6 g.

       \ vskip1.000000 \ baselineskip
    

I-9) 4- (7-Acetylamino-3-phenyl-4,5-dihydro-pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1-yl) - 3-chlorobenzoic

52

Similarly to the preparation of I-4, starting from Z-11 (2.3 g, 7.1 mmoles) and 3-chloro-4-hydrazinobenzoate of methyl (1.8 g, 8.5 mmol), the desired compound is obtained. Yield: 0.36 g.

I-10) N - [1- (2-Chloro-4-nitro-phenyl) -3-phenyl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1, 2- d ] thiazol-7-yl] -acetamide

       \ vskip1.000000 \ baselineskip
    

53

Similarly to the preparation of I-1, starting from Z-11 (7.5 g, 13.1 mmol) and 3-chloro-4-hydrazinonitroben-
Ceno (3.2 g, 14.4 mmol) in 100 ml of glacial acetic acid, the desired product is obtained. Yield: 1.1 g.

       \ vskip1.000000 \ baselineskip
    

I-11) N - (1-piperidin-4-yl-3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl) -acetamide

       \ vskip1.000000 \ baselineskip
    

54

Similarly to the preparation of I-1, starting from Z-12 (2.5 g, 7.9 mmol) and H-5 (1.2 g, 7.9 mmol) in 50 ml of glacial acetic acid, stirred 15 h at 60 ° C. The mixture is poured over ice water and made alkaline with 1 N sodium hydroxide (pH 12). The resulting precipitate is filtered, washed with water and dried to 40 ° C making vacuum. Yield: 2 g.

       \ vskip1.000000 \ baselineskip
    

I-12) 4- (7-Acetylamino-3-pyridin-3-yl-4,5-dihydro-pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1- acid il) -cyclohexane-carboxylic

       \ vskip1.000000 \ baselineskip
    

55

Similarly to the preparation of I-4, starting from Z-12 (1.9 g, 5.8 mmol) and H-6 (1.3 g, 5.8 mmol), the desired compound. Yield: 0.78g.

The corresponding cis or trans compounds are obtained by using the pure cis isomer H-6 or trans H-6.

       \ newpage
    

Other intermediate compounds, which may prepare analogously to the synthesis above described:

       \ vskip1.000000 \ baselineskip
    

56

       \ newpage
    

(Continuation)

57

       \ newpage
    

(Continuation)

58

       \ newpage
    

(Continuation)

59

       \ vskip1.000000 \ baselineskip
    

II-1) N - [1- (4-amino-2-chlorophenyl) -3-furan-2-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [ 1,2- d ] thiazol-7-yl] -acetamide

       \ vskip1.000000 \ baselineskip
    

60

       \ vskip1.000000 \ baselineskip
    

A solution of I-4 (2.1 g, 4.6 mmol) in 20 ml of DMF is mixed with diphenylphosphorylazide (1.1 ml, 5 mmol) and with 0.7 ml of triethylamine and stirred 6 h at 50 ° C. To the reaction mixture is added p- toluenesulfonic acid (1.5 g, 9.1 mmol) and 3 ml of water, and stir 39 h at 50 ° C. The mixture is then poured onto 300 ml of ice water and the resulting precipitate is filtered. The residue is purified by chromatography on silica gel, with dichloromethane: methanol: 98: 2: 0.2 ammonia. Yield: 0.6 g.

       \ vskip1.000000 \ baselineskip
    

II-3) N - [1- (4-amino-2-chlorophenyl) -3-phenyl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl] -acetamide

       \ vskip1.000000 \ baselineskip
    

61

       \ vskip1.000000 \ baselineskip
    

A solution of I-10 (1.1 g, 2 mmoles) in 20 ml of glacial acetic acid mixed with powder iron (0.77 g, 13.8 mmol) and stir 4 h at 70 ° C. After filter over diatomaceous earth, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel, with dichloromethane: 99: 1 methanol. Yield: 0.8 g.

       \ vskip1.000000 \ baselineskip
    

II-4) N - [1- (4-aminophenyl) -3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl] -acetamide

62

In a manner analogous to the preparation of II-2, starting from I-16 (0.2 g, 0.5 mmoles) the desired product is obtained. Yield: 0.14 g.

       \ vskip1.000000 \ baselineskip
    

II-5) N - [1- (3-aminophenyl) -3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl] -acetamide

63

In a 250 ml hydrogenation reactor, suspend I-17 (1.2 g, 2.8 mmol) in 150 ml of methanol The suspension is mixed with palladium (5% on carbon active, 120 mg) and stirred at RT and 50 psi of hydrogen pressure. TO at 18 and 40 h the same amount is added again, respectively of catalyst. After another 15 h the catalyst is separated by filtration and the solvent is removed in vacuo. Yield: 0.89 g.

       \ vskip1.000000 \ baselineskip
    

II-6) N - [1- (4-amino-2-chlorophenyl) -3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [ 1,2- d ] thiazol-7-yl] -acetamide

64

In a manner analogous to the preparation of II-3, starting from I-18 (10 g, 21 mmoles) the desired product is obtained. Yield: 8.4 g.

       \ vskip1.000000 \ baselineskip
    

II-9) [4- (7-Acetylamino-3-phenyl-4,5-dihydro-pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1-yl) - Ethyl 3-chlorophenyl] -thiocarbamate

65

To a solution of II-6 (3 g, 5.8 mmoles) in 75 ml of pyridine, chloroformate of ethyl (0.7 ml) and stir 4 h at RT. After removing pyridine in a rotary evaporator, the residue is collected with water and the precipitate is filtered. A solid is obtained, which is dried for 15 h at 60 ° C under vacuum. Yield: 3 g.

       \ vskip1.000000 \ baselineskip
    

II-10) N - [1- (4-aminomethyl-2-chlorophenyl) -3-phenyl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl] -acetamide

66

A solution of I-8 (1.5 g, 3.3 mmol) in 150 ml of ammoniacal methanol is mixed with 20 mg of Raney nickel and stir for 15 h at RT under hydrogen atmosphere (3.5 bar). The mixture is dissolved in dichloromethane and filtered to through silica gel. After removing the solvent in vacuo, the residue is crystallized from a solution in diethyl ether / ether of Petroleum. Yield: 1.1 g.

       \ vskip1.000000 \ baselineskip
    

II-11) N - [1- (2-Chloro-4-formyl-phenyl) -3-pyrazin-2-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl] -acetamide

67

A solution of I-29 (0.5 g, 1.1 mmol) in 25 ml of acetone is mixed with 2 g of manganese and boil 3 h at reflux. Then the Reactant mixture and the solvent is removed in vacuo. Yield: 0.25 g.

       \ vskip1.000000 \ baselineskip
    

II-12) N - [1- (3-aminomethyl) -3-phenyl) -4,5-dihydro-1 H -pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl] -acetamide

68

In a manner analogous to the preparation of II-10, starting from I-38 (2.3 g, 5.6 mmoles) the desired product is obtained. Yield: 1.4 g.

       \ vskip1.000000 \ baselineskip
    

II-13) N - [1- (4-amino-2-fluorophenyl) -3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [ 1,2- d ] thiazol-7-yl] -acetamide

69

In a manner analogous to the preparation of II-3, starting from I-39 (1 g, 2.2 mmoles) the desired product is obtained. Yield: 1 g.

       \ vskip1.000000 \ baselineskip
    

II-14) 4- (7-amino-3-pyridin-3-yl-4,5-dihydro-pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1- il) - N, N- dimethyl-benzamide

       \ vskip1.000000 \ baselineskip
    

70

       \ vskip1.000000 \ baselineskip
    

A solution of I-20 (6.3 g, 14.5 mmol) in 150 ml of dioxane is mixed with 10 ml of acid concentrated hydrochloric and 100 ml of water and heated 6 h at Reflux. The clear solution is stirred an additional 16 h at 50 ° C and then it is concentrated in vacuo to dryness. The product deacetylated (6.6 g, 14 mmol) is dissolved in 150 ml of DMF and is mixture with TBTU (5.1 g, 15 mmol) and 10 ml of triethylamine. The Reactant mixture is stirred 30 min. at TA, mix with dimethylamine hydrochloride (1.25 g, 15 mmol) and stir another 6 h to TA After hydrolyzing with 1 l of water, the precipitate resulting is filtered and dried in vacuo. Yield: 5.5 g.

       \ vskip1.000000 \ baselineskip
    

II-15) 4- (7-amino-3-pyridin-3-yl-4,5-dihydro-pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1- il] -3-chloro- N, N -dimethyl-benzamide

       \ vskip1.000000 \ baselineskip
    

71

       \ vskip1.000000 \ baselineskip
    

A solution of example 2.180 (500 mg, 1 mmol) mixed with 5.5 ml of hydrochloric acid (4 M in dioxane) and 5.5 ml of water and heated 2.5 h at 80 ° C. The clear solution is Stir an additional 15 h at 70 ° C and then concentrate in vacuo to dryness. Yield: 580 mg.

       \ vskip1.000000 \ baselineskip
    

II-16) 4- (7-amino-3-pyridin-3-yl-4,5-dihydro-pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-1- il] -3-fluoro- N, N -dimethyl-benzamide

       \ vskip1.000000 \ baselineskip
    

72

       \ vskip1.000000 \ baselineskip
    

A solution of Example 2.182 (1.37 mg, 2.9 mmol) is mixed with 30 ml of hydrochloric acid (37%) and with 35 ml of water and heated 12 h at 50 ° C. After concentrating under vacuum The residue is diluted in water and mixed with 4 N sodium hydroxide. The resulting precipitate is filtered and dried. Yield: 1.1 g.

       \ vskip1.000000 \ baselineskip
    

II-17) 1- (2-Chlorophenyl) -3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazole -7-ylamine

73

In an analogous way to the preparation of the example II-16, starting from I-46 (10.3 g, 24 mmol) and 280 ml of hydrochloric acid (37%) in 330 ml of water the desired product is obtained. Yield: 7.6 g.

       \ vskip1.000000 \ baselineskip
    

II-18) 1-phenyl-3-pyridin-3-yl-4,5-dihydro-1 H -pyrazolo- [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7- ilamine

74

Analogous to the preparation of II-16, from example 1.13 (7.7 g, 20 mmol) and 50 ml of hydrochloric acid (37%) in 30 ml of water, the desired product is obtained. Yield: 6.8 g of II-19) 4- (7-amino-3-pyridin-3-yl-4,5-dihydro-pyrazolo- [3 ', 4': 3,4] benzo [1, 2- d ] thiazol-1-yl) -3-chlorobenzoic.

75

Analogous to the preparation of the compound intermediate II-16, from example 1.21 (2.9 g, 5 mmol) and 2 ml of hydrochloric acid (32%) in a mixture of 10 ml of water and 20 ml of dioxane, the desired product is obtained. Yield: 2.7 g.

       \ vskip1.000000 \ baselineskip
    

Analytical methods

Method AM1

HPLC:

Agilent 1100 series; MS: 1100 series LC / MSD

quad

(API-ES (+/- 3000 V, Quadrupol, G1946D);

Operating Mode:

Scan pos 100-1000, neg 100-1000

Column:

Waters; part no. 186000594; XTerra MS C18 2.5 \ mum; 2.1 x 50 mm column

Solvent:

A: Desalinated H2O with 0.1% addition of formic acid

quad

B: HPLC purity acetonitrile with 0.1% addition of formic acid

Detection:

peak width> 0.1 min. (2s); 190-450 nm

quad

UV 254 nm (bandwidth 8, reference disconnected)

quad

UV 230 nm (bandwidth 8, reference disconnected)

Injection:

1 µl standard injection, flow rate: 0.6 ml / min., column temperature: 35 ° C

       \ newpage
    

Pumping Gradient:

0.0-0.5 min.

5% of B

0.5-1.5 min.

5% -> 50% of B

1.5-4.0 min.

50% -> 95% of B

4.0-6.0 min.

95% of B

6.0-6.5 min.

95% -> 5% of B

1.5 min. post elution

5% of B

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Method AM2

HPLC:

Agilent 1100 series (G1379A / G1310A reset as 1311A / G1313A / G1316A / G1948D / G1315B / G1946D);

Operating Mode:

Scan pos 100-1000, neg 100-1000

Column:

Agilent Zorbax SB-C8, 2.1 x 50 mm, 3.5 µm

Solvent:

A: Desalinated H2O with 0.1% addition of formic acid

quad

B: HPLC purity acetonitrile with 0.1% addition of formic acid

Detection:

peak width> 0.1 min. (2s); 190-450 nm

quad

UV 254 nm (bandwidth 8, reference disconnected)

quad

UV 230 nm (bandwidth 8, reference disconnected)

Injection:

2.5 µl standard injection, flow: 0.6 ml / min., column temperature: 35 ° C

Pumping Gradient:

0.0-3.0 min.

10% -> 90% of B

3.0-4.0 min.

90% of B

4.0-5.0 min.

90% -> 10% of B

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Method AM3

HPLC:

Agilent 1100 series (G1312A / G1315A / G1316A / G1367A); Agilent MSD SL ESI;

Operating Mode:

Scan pos 150-750

Column:

Agilent Zorbax SB-C8, 2.1 x 50 mm, 3.5 µm

Solvent:

A: Desalinated H2O with 0.1% addition of formic acid

quad

B: HPLC purity acetonitrile with 0.1% addition of formic acid

Detection:

peak width> 0.01 min. (0.2s); 190-450 nm

quad

UV 254 nm (bandwidth 16, reference disconnected)

quad

UV 230 nm (bandwidth 8, reference disconnected)

quad

UV 214 nm (bandwidth 8, reference disconnected)

Injection:

3.5 µl overlap injection, flow: 1.1 ml / min., column temperature: 45 ° C

Pumping Gradient:

0-1.75 min.

15% -> 95% of B

1.75-1.90 min.

95% of B

1.90-1.92 min.

95% -> 15% of B

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Method AM4

HPLC:

Agilent 1100 series

MS:

Agilent LC / MSD SL (LCMS1: 1100 series LC / MSD)

Column:

Waters, XTerra MS C18, 2.5 µm, 2.1 x 30 mm, part no. 186000592

Solvent:

A: Desalinated H2O with 0.1% addition of formic acid

quad

B: HPLC purity acetonitrile with 0.1% addition of formic acid

Detection:

MS: {} \ hskip3.5cm positive and negative

Interval masses:

120-900 m / z

Fragmenter:

120

MEV of amplitude:

one

Threshold:

150

Step size:

0.25

UV:

254 nm

Bandwidth:

1 (LCMS1: 2)

Reference:

disconnected

Spectrum:

Range: {} \ hskip2.8cm 250-400 nm

Step of interval:

1.00 nm

Threshold:

4.00 mAU

Peak width:

<0.01 (LCMS1:> 0.05 min)

Slit:

1 nm (LCMS1: 2 nm)

Injection:

5 \ mul

Flow:

1.10 ml / min.

Temperature of column:

40 ° C

Gradient:

0.00 min.

5% of B

0.00-2.50 min.

5% -> 95% of B

2.50-2.80 min.

95% of B

2.81-3.10 min.

95% -> 5% of B

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Method AM5

HPLC:

Agilent 1100 series

MS:

Agilent LC / MSD SL (LCMS1: 1100 series LC / MSD)

Column:

Phenomenex, Synergi Polar RP 80A, 4, 2.0 x 30 mm, part no. 00A-4336-B0

Solvent: A:

H2O (Millipore maximum purity water) with 0.1% of HCOOH

quad

B: HPLC purity acetonitrile

Detection:

MS: {} \ hskip3.5cm positive and negative

Interval masses:

120-900 m / z

Fragmenter:

120

MEV of amplitude:

one

Threshold:

150

Step size:

0.25

UV:

254 nm

Bandwidth:

1 (LCMS1: 2)

Reference:

disconnected

Spectrum:

Range: {} \ hskip2.8cm 250-400 nm

Step of interval:

1.00 nm

Threshold:

4.00 mAU

Peak width:

<0.01 (LCMS1:> 0.05 min)

Slit:

1 nm (LCMS1: 2 nm)

Injection:

vol. 5 \ mul

Modality of injection:

needle wash

Separation:

Flow: {} \ hskip3.3cm 1.10 ml / min.

Temperature of column:

40 ° C

Gradient: 0.00 min.

\ hskip1.6cm5% of B

0.00-2.50 min.

5% -> 95% of B

2.50-2.80 min.

95% of B

2.81-3.10 min.

95% -> 5% of B

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Method AM6

HPLC:

Waters Alliance 2695

MS:

Agilent LC / MSD SL (LCMS1: 1100 series LC / MSD)

Column:

Waters, XTerra MS C18, 2.5 µm, 4.6 x 30 mm part number 186000600

       \ newpage
    

Solvent:

A: Desalinated H2O, with the addition of 0.1% of formic acid

quad

B: HPLC purity acetonitrile, with the addition of 0.08% formic acid

Flow:

1 ml / min

Temperature of column:

25ºC

Gradient:

0.00 min. {} \ hskip2,8cm 5% of B

0.00-3.10 min.

5% -> 98% of B

3.10-4.50 min.

98% of B

4,50-5.00 min.

98% -> 5% of B

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Abbreviations used

d

day

DC

thin layer chromatography

DCM

dichloromethane

DMAP

N, N- dimethylaminopyridine

DMF

N, N- dimethylformamide

DMSO

dimethylsulfoxide

EtOH

ethanol

h

hour

HEY YOU

O - (7-azabenzotriazol-1-yl) - N, N, N, N ' -tetramethyluronium-hexafluorophosphate

HPLC

high liquid chromatography performance

conc.

concentrated

Li-HMDS

lithium hexamethyldisilazane

M

cool

MeOH

methanol

min.

minutes

ml

milliliters

MS

mass spectrometry

N

normal

NMR

nuclear resonance spectroscopy

ppm

parts per million

Rf

retention factor

RP

reverse phase

TA

room temperature

Rt

holding time

Pf

melting point

TBTU

O- benzotriazol-1-yl- N, N, N ', N' -tetramethyluroniotetra-fluoroborate

tert

tertiary

THF

tetrahydrofuran

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

Examples 1.1-1.13

       \ vskip1.000000 \ baselineskip
    

76

       \ vskip1.000000 \ baselineskip
    

The preparation of the examples 1.1-1.13 takes place analogously to the synthesis I-1

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

77

(Continuation)

78

       \ newpage
    

(Continuation)

79

Example 2 Reaction of carboxylic acids with amines

Synthesis method TO

A solution of the carboxylic acid (0.1 mmol) in 5 ml of dichloromethane it is mixed with TBTU (0.15 mmol) and triethyl amine (0.65 mmol) and stir 15 min. to TA. The corresponding amine (0.1 mmol) is then added and Stir at RT until the reaction is complete. The reaction mixture it is combined with 5% aqueous solution of potassium carbonate and extract with dichloromethane. The combined organic phases are dried and They are concentrated in vacuo. The residue is recrystallized from a solution in petroleum ether or chromatographically purified.

       \ vskip1.000000 \ baselineskip
    

Synthesis method B

A solution of the carboxylic acid (0.35 mmol) in 5 ml of DMF (or dichloromethane or THF) it is mixed with HATU (0.55 mmol) and diisopropylethylamine (1.8 mmol) and stirred for 15 min. to TA. After adding the corresponding amine (0.39 mmol) stirred at 15 h at RT, mixed with 5% aqueous solution of potassium carbonate and extracted with dichloromethane. Phases The combined organics are dried and concentrated in vacuo. The residue is Purify chromatographically.

       \ vskip1.000000 \ baselineskip
    

Synthesis method C

This synthesis is performed analogously to synthesis method B, but using triethylamine instead of diisopropyl ethylamine.

       \ vskip1.000000 \ baselineskip
    

Synthesis method D

In the first place the acid is immobilized carboxylic in a polymer. For this, 1.2 g of resin are mixed PL-TFP (1.25 mmol / g, 150-300 \ mum; Polymer Laboratories) with 12 ml of dichloromethane and 5 min. then the corresponding one is added successively with a pipette carboxylic acid (1.2 mmol in 6 ml DMF), DMAP (0.7 mmol in 6 ml of dichloromethane) and 0.8 ml of diisopropylcarbodiimide. The mixture is allowed to stand 36 h at RT. The resin is separated by filtration through a glass frit (porosity 4) and lava, respectively, with 4 x 15 ml of DMF, 4 x 20 ml of dichloromethane and 4 x 20 ml of THF, so that each solvent drip through the frit without vacuum or pressure and drying by aspiration before passing each new solvent. The washed resin is dry 2 h at RT and 0.2 mbar. Yield of dry resin: 2,204 g.

To react the carboxylic acid immobilized 110 mg (0.15 mmol) of the resin are incorporated as well prepared to 1 ml of dichloromethane and 0.5 ml of DMF and mixed with amine (0.1 mmol) and diisopropylethylamine (0.1 mmol). TO The mixture is then slowly stirred 15 h at RT. At the end of the reaction the resin is filtered as described above and wash with 8 x 3 ml dichloromethane. The filtrate is concentrated at vacuum and the residue is purified by RP-HPLC.

       \ newpage
    

Examples 2.1-2.183

80

(Continuation)

81

       \ newpage
    

(Continuation)

82

(Continuation)

83

(Continuation)

84

       \ newpage
    

(Continuation)

85

       \ newpage
    

(Continuation)

86

       \ newpage
    

(Continuation)

87

       \ newpage
    

(Continuation)

88

       \ newpage
    

(Continuation)

89

       \ newpage
    

(Continuation)

90

       \ newpage
    

(Continuation)

91

       \ newpage
    

(Continuation)

92

       \ newpage
    

(Continuation)

93

       \ newpage
    

(Continuation)

94

       \ newpage
    

(Continuation)

95

       \ newpage
    

(Continuation)

96

       \ newpage
    

(Continuation)

97

       \ newpage
    

(Continuation)

98

       \ newpage
    

(Continuation)

99

       \ newpage
    

(Continuation)

100

       \ newpage
    

(Continuation)

101

       \ newpage
    

(Continuation)

102

       \ newpage
    

(Continuation)

103

       \ newpage
    

(Continuation)

104

       \ newpage
    

(Continuation)

105

       \ newpage
    

(Continuation)

106

       \ newpage
    

(Continuation)

107

       \ newpage
    

(Continuation)

108

       \ newpage
    

(Continuation)

109

       \ newpage
    

(Continuation)

110

       \ newpage
    

(Continuation)

111

       \ newpage
    

(Continuation)

112

       \ newpage
    

(Continuation)

113

       \ newpage
    

(Continuation)

114

       \ newpage
    

(Continuation)

115

       \ vskip1.000000 \ baselineskip
    

Examples 3

Reaction of prepared amines

Synthesis method AND

Reaction with sulfonic acid chlorides

A solution of 0.2 mmol of amine in 3 ml of Pyridine is mixed with 0.5 mmol of sulfonic acid chloride and stir for 15 h at RT. The reaction mixture is concentrated and the residue is chromatographically purified.

       \ vskip1.000000 \ baselineskip
    

Synthesis method F

Reaction with carboxylic acids

A solution of the carboxylic acid (0.16 mmol) in 1.3 ml of DMF is mixed with HATU (0.55 mmol) and diisopropyl ethylamine (1.8 mmol) and stir 1 h at TA After adding a solution of the corresponding amine in DMF, stir for another 15 hours at RT. Then the reaction mixture is filter, concentrate and the residue is purified chromatographically

       \ vskip1.000000 \ baselineskip
    

Synthesis method G

Reaction with carboxylic acid chlorides

A solution of 0.2 mmol of amine in 3 ml of Pyridine is mixed with 0.5 mmol of carboxylic acid chloride and Stir for 15 h at RT. The reaction mixture is concentrated and the residue is chromatographically purified.

       \ newpage
    

Examples 3.2-3.82

116

       \ newpage
    

(Continuation)

117

       \ newpage
    

(Continuation)

118

       \ newpage
    

(Continuation)

119

       \ newpage
    

(Continuation)

120

       \ newpage
    

(Continuation)

121

       \ newpage
    

(Continuation)

122

       \ newpage
    

(Continuation)

123

       \ newpage
    

(Continuation)

124

       \ newpage
    

(Continuation)

125

       \ newpage
    

(Continuation)

126

       \ newpage
    

(Continuation)

127

       \ newpage
    

(Continuation)

128

       \ newpage
    

(Continuation)

129

       \ newpage
    

(Continuation)

130

       \ vskip1.000000 \ baselineskip
    

Examples 4

Reaction of thiocarbamates with amines and alcohols Urea Preparation

A solution of 0.11 mmol of thiocarbamate in 5 ml of ethanol is mixed with 0.17 mmol of amine and 30 µl of diisopropylethylamine and stir 15 h at 80 ° C in a pressure tube. After removing the solvent in vacuo, the residue is purified chromatographically

       \ vskip1.000000 \ baselineskip
    

Carbamate Preparation

A solution of 0.11 mmol thiocarbamate (or methyl carbamate) is mixed with 5 ml of the corresponding alcohol and stir 15 h at 80 ° C in a pressure tube. After deleting the solvent under vacuum, the residue is chromatographically purified.

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

       \ newpage
    

Examples 4.1-4.32

131

       \ newpage
    

(Continuation)

132

       \ newpage
    

(Continuation)

133

       \ newpage
    

(Continuation)

134

       \ newpage
    

(Continuation)

135

       \ newpage
    

(Continuation)

136

       \ newpage
    

Examples 5

Chloropyridyl units reaction

137

Synthesis method H

When the amines are in liquid form, they dissolve 0.2 mmol of the chloropyridine unit in 0.5 ml of amine and it is heated at 120 ° C in the microwave (CEM) for 10 min. After remove the excess amine the residue is purified chromatographically

       \ vskip1.000000 \ baselineskip
    

Synthesis method I

A solution of 1.2 mmol of the unit chloropyridine and 3 mmol of amine in 3 ml of N-methylpyrrolidinone, DMSO or DMF is heated to 120 ° C in the microwave (CEM) for 10 min. After removing the solvent and The excess amine is purified chromatographically.

       \ vskip1.000000 \ baselineskip
    

Examples 5.1-5.23

       \ vskip1.000000 \ baselineskip
    

138

       \ newpage
    

(Continuation)

139

       \ newpage
    

(Continuation)

140

       \ newpage
    

(Continuation)

141

       \ newpage
    

(Continuation)

142

       \ newpage
    

(Continuation)

143

       \ vskip1.000000 \ baselineskip
    

Examples 6

Reductive amination

Method J

A solution of 70 mg of II-10 (0.15 mmol) and 22 µL of N- methylpiperidin-4-one (0.18 mmol) in 5 ml of dichloromethane is stirred for 2 h at RT. After adding 40 mg of sodium triacetoxyborohydride (0.18 mmol) the reaction mixture is stirred an additional 15 h. The mixture is diluted with dichloromethane, washed with dilute sodium bicarbonate solution and the organic phases are dried and concentrated. The residue is dissolved in a very small amount of ethyl acetate / methanol and crystallized with diethyl ether. The precipitated crystals are filtered and then dried under vacuum.

       \ vskip1.000000 \ baselineskip
    

Method K

A solution of 220 mg of II-11 (0.5 mmol) and 0.1 ml of benzylamine (1 mmol) in 5 ml of methanol are stir for 15 h at 60 ° C and then mix with 155 mg of sodium triacetoxyborohydride (0.7 mmol) and 40 mg of sodium acetate (0.5 mmol). After hydrolyzing with sodium bicarbonate and extract with dichloromethane, the organic phase is dried and concentrated and the residue is purified cormatographically.

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

       \ newpage
    

Examples 6.1-6.4

144

Examples 7

Synthesis method L

Cross coupling with arylboronic acids

A 100 mg suspension of I-24 (0.2 mmol) in 3 ml of acetone is mixed with the corresponding boronic acid Then 4.4 mg of acetate are added palladium (II) (19 µmoles), 4 µl of diazabicyclooctane (39 µmoles) and 80 mg of potassium carbonate and the container of reaction is heated 20 min. at 100 ° C in the microwave and then two more times, 40 min. at 120 ° C and 70 ° C respectively. After remove the solvent the reaction mixture is purified chromatographically

Synthesis method M

Cross coupling with alkynes

At a solution of 200 mg of I-31 (0.3 mmol), 6 mg of copper (I) iodide (34) and 24 mg of triphenylphosphine palladium (II) chloride (34) in 25 ml of Degassed THF is added, under stirring and under argon, 56 mg of N, N- dimethylaminoprop-2-ino (0.7 mmol) and the reaction mixture is stirred 15 h at 80 ° C. 100 µL of alkyne, as well as 10 mg of CuI and 20 mg of Pd catalyst are added and left for another 24 h under stirring at 55 ° C. It is basified with aqueous NH 3 solution, diluted with water and extracted 2 x with THF. The combined organic phases are stirred with saturated NaCl solution, dried and concentrated. The residue is chromatographically purified.

       \ vskip1.000000 \ baselineskip
    

Synthesis method N

Palladium Catalyzed Amination

At a solution of 200 mg of I-31 (0.3 mmol), 38 mg of 4-aminopyridine (0.4 mmol), 47 mg of tris (dibenzylidene acetone) dipaladium (51 µmoles), 111 mg of tert -sodium butylate (1 mmol) in 4 ml of degassed DMF is added 30 mg of tri- tert -butyl phosphitetrafluoroborate and stirred 4 h at 90 ° C under an argon atmosphere. After hydrolyzing with phosphate buffer and water, it is extracted with dichloromethane. The organic phase is dried, filtered and concentrated, and the residue is chromatographically purified.

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

       \ vskip1.000000 \ baselineskip
    

(Table goes to page next)

       \ newpage
    

Examples 7.1-7.8

145

       \ newpage
    

(Continuation)

146

       \ vskip1.000000 \ baselineskip
    

Example 8

147

60 mg of N - (3-hydrazinocarbonyl-1-phenyl-4,5-dihydro-1 H -pyrazolo [3 ', 4': 3,4] benzo [1,2- d ] thiazol-7-yl) - acetamide
(0.16 mmol) - which can be obtained according to the method of synthesis B, starting with I-6 and hydrazine - are treated with 3 ml of triethyl orthoformate for 30 min. at 180 ° C in the microwave. After removing the excess orthoester in vacuo, the residue is chromatographically purified. Yield: 4 mg.

[M + 1] + = 379.

Rt = 1.75 min.

       \ newpage
    

Examples 9.1-9.4

In a manner analogous to the synthesis of the example II-2 the following compounds are prepared.

148

The following example describes the action Biological of the compounds of the present invention, without intending Limit it to this example.

       \ vskip1.000000 \ baselineskip
    

Cytotoxicity test with HCT116

The trial is based on the reduction of AlamarBlue (Biosource Int., USA) in living cells (metabolically active) a a product detectable by fluorometry. In the presence of cytotoxic substances cannot reduce the substrate and therefore no increase in fluorescence can be measured.

HCT116 cells (cell line of the human colon carcinoma) in microtiter plates and incubate during overnight in a culture medium at 37 ° C with 5% CO2. The analyzed substances are gradually diluted in the medium and they add to the cells, so that the total volume is 200 \ mul / well. As a control, cells mixed with medium are used, But not with substance. After an incubation time of 4-6 days 20 µl / well of AlamarBlue are added and the cells are incubated at 37 ° C for a further 6-8 h. To measure the fluorescence is excited at a wavelength of 545 nm and the emission at 590 nm is measured.

EC_ {50} values are calculated with the help of the GraphPad Prism program.

All the mentioned examples present a EC50 value (HCT-116) less than 5 µM.

The substances of the present invention are PI3 kinase inhibitors. Thanks to its biological properties the new compounds of the general formula (1), their isomers and their Physiologically compatible salts are appropriate for treatment of diseases characterized by cell proliferation excessive or anomalous

These diseases include, for example: viral infections (eg HIV and Kaposi's sarcoma); inflammations and autoimmune diseases (eg colitis, arthritis, disease of Alzheimer's, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; leukemia, solid lymphomas and tumors; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. ex. restenosis and hypertrophy). They are also useful for protecting proliferating cells (eg hair, intestinal cells, blood and progenitor) against DNA damage caused by radiation and UV and / or cytostatic treatments (Davis and others, 2001).

With the compounds of the present invention, the following cancerous diseases can be treated, for example, without limitation: brain tumors such as acoustic neuromas, astrocytomas such as those of the pilocytic, fibrillar, protoplasmic, gemistocytic, anaplastic and gioblastomas type , brain lymphomas, brain metastases, pituitary tumors such as prolactinoma, tumor producing HGH (human growth hormone) and tumor producing ACTH (adrenocorticotropic hormone), craniopharyngomas, medulloblastomas, meningiomas and oligodendrogliomas; Nerve tumors (neoplasms) such as those of the vegetative nervous system such as sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma, chromafinoma) and glomus caroticum tumor, peripheral nervous system tumors such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, schwannoma ) and malignant schwannoma, as well as tumors in the central nervous system in the form of brain or spinal cord tumors; intestinal cancer, such as rectal carcinoma, colon carcinoma, anal carcinoma, tumors of the small intestine and duodenal; eyelid tumors such as basalioma or basal cell carcinoma; pancreatic cancer or pancreatic carcinoma; lung cancer (bronchial carcinoma) such as small cell (oat cell carcinomas) and non-small cell bronchial carcinomas, such as squamous epithelial carcinomas, adenocarcinomas and bronchial carcinomas of large cells; breast cancers, for example breast carcinoma in the form of infiltrating ductal carcinoma, colloidal carcinoma, invasive lobular carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin lymphomas (NHL) such as Burkitt lymphoma, non-Hodgkin lymphomas (NHL) of low malignancy and fungoid mucosis, uterine cancer or endometrial or uterine body carcinoma; CUP syndrome (cancer of unknown primary origin; ovarian cancer or ovarian carcinoma, such as mucinosis, endometrial or serous cancer; gallbladder cancer; bile duct cancer, such as Klatskin's tumor; testicular cancer, for example seminomas and not seminomas; lymphoma (lymphosarcoma), such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukemia, hair cell leukemia, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt lymphoma, fungoid mycosis T-cell, anaplastic large cell lymphoblastoma, and lymphoblastoma; larynx cancer, such as vocal cord tumors, supraglottic, glotic and subglottic larynx tumors; bone cancers, such as osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteoids arcoma, Ewing's sarcoma, reticular sarcoma, plasmacytoma, fibrous dysplasia, juvenile bone cyst and aneurysmal bone cyst; head and neck tumors, such as those of the lips, tongue, oral base, mucosa of the oral cavity, palate, salivary glands, pharynx, nasal passages, perinasal cavities, larynx and middle ear; liver cancer, such as liver carcinoma or hepatocellular carcinoma (HCC); leukemias, such as acute leukemias such as acute lymphoblastic / lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); chronic leukemias, such as chronic lymphatic leukemia (CLL), chronic myeloid leukemia (CML); stomach cancer or gastric carcinoma, such as papillary, tubular and mucinous adenocarcinoma, adenoescamosal cell carcinoma of the seal ring, small cell carcinoma and undifferentiated carcinoma; melanomas, such as those of superficially disseminated type, nodular, malignant lentiginous and acral lentiginous; kidney cancer, such as renal cell carcinoma or hypernephroma or Grawitz tumor; esophageal cancer or esophageal carcinoma; penile cancer; prostate cancer; pharyngeal cancer or pharyngeal carcinomas such as nasopharyngeal carcinomas, oropharyngeal and hypopharyngeal carcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma; squamous epithelial carcinomas, adenocarcinomas, carcinomas in situ , melanomas and malignant sarcomas; thyroid carcinomas, for example those of papillary, follicular and medullary type, as well as anaplastic carcinomas; spinalioma, squamous cell carcinoma and squamous epithelial carcinoma of the skin; thymomas, urethral cancer and vulvar cancer.

The new compounds can be used for prevention and short or long term treatment of diseases mentioned above, also, if necessary, in combination with other compounds of the current technical state, such as for example other antitumor, cytotoxic, inhibitory substances of cell proliferation, antiangiogens, steroids or antibodies

The compounds of the general formula (1) are can use alone or in combination with other active ingredients as  to the present invention, also, if necessary, in combination with Other active pharmacological principles. The agents chemotherapeutics that can be administered in combination with Compounds of the present invention encompass, without limitation, hormones, substances analogous to hormones and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, acetate megestrol, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (eg anastrozole, letrozole, liarozole, vorozol, exemestane, atamestane), LHRH agonists and antagonists (eg goserelin acetate, luprolid), inhibitors of growth (growth factors such as: "factor of platelet-derived growth "and" growth factor of hepatocytes "inhibitors are, eg, the antibodies of "growth factors", the receptor antibodies of "growth factors" and inhibitors of tyrosine kinases, such as gefinitib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as metrotrexate, raltitrexed, compound analogous to pyrimidine such as 5-fluorouracil, capecitabine and gemcitabine, purine and adenosine analog compounds such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumor antibiotics (eg anthracyclines such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (such as cisplatin, oxaliplatin, carboplatin); alkylating agents (eg estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas as per example carmustine and lomustine, thiotepa); antimitotic agents (e.g. ex. vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (eg epipodophyllotoxins as per example etoposide and etophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone) and different chemotherapeutic agents such as amifostine, anagrelide, clodronate, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porphimer.

For example, tablets, capsules, suppositories, solutions -special- are suitable
mind solutions for injection (sc, iv, im) and infusions - syrups, emulsions or dispersible powders. Its proportion of active pharmaceutical compound (s) is respectively in the range of 0.1-90% by weight, especially 0.5-50% by weight, based on the entire composition, i.e. , in sufficient quantities to reach the dosage range indicated below. If necessary, the said doses can be administered several times a day.

For example, tablets can be obtained suitable by mixing the active substance (s) with substances known auxiliaries, for example inert diluents such as carbonate calcium, calcium phosphate or lactose, disintegrating agents such as cornstarch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the deposit effect, such as carboxymethyl cellulose, cellulose acetaphthalate or polyvinyl acetate. The tablets can also consist of several layers.

Suitable dragees can be prepared by coating nuclei made analogously to tablets with usual products in the coating of dragees, for example Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a deposit effect or to avoid incompatibilities, the core can also consist of several layers. Also, the dragee wrap may also include of several layers to achieve a deposit effect, being able to use the auxiliary substances mentioned above in the case of tablets.

Syrups with active ingredients or combinations of active ingredients of the present invention can also contain a sweetener such as saccharin, cyclamate, glycerin or sugar, as well as a product to improve flavor, e.g. ex. flavorings such as vanilla or orange extract. They can also carry suspending or thickening agents such as carboxymethyl cellulose sodium, humectants, such as condensation products of fatty alcohols with ethylene oxide, or protective agents such as p-hydroxybenzoates.

Injection and infusion solutions are prepare as usual, p. eg, adding isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkaline acid salts ethylenediaminetetraacetic acid, and, if necessary, using emulsifiers and / or dispersants. When water is used as a diluent organic solvents can also be added as solubilizers or dissolution aids. These solutions are packed in blisters. or in infusion bottles.

Capsules containing one or more principles assets or combinations of active principles herein invention can be prepared, for example, by mixing the principles assets with an inert support, such as lactose or sorbitol, and introducing them in gelatin capsules. They can be made suitable suppositories, for example, by mixing with supports intended for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

As auxiliary substances it is possible to mention, by example, water; pharmaceutically safe organic solvents, such as paraffins (eg oil fractions), oils of origin vegetable (eg peanut or sesame oil), mono alcohols or polyfunctional (eg ethanol or glycerin); supports, such as p. ex. natural ground minerals (eg kaolins, clays, talc, Cretas) or synthetics (eg silica and highly silicate scattered); sugars (e.g. cane, lactose and glucose), emulsifiers (e.g., lignin sulphite bleach, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg stearate magnesium, talc, stearic acid and sodium lauryl sulfate).

Administration is carried out in the usual way, preferably orally or transdermally, especially orally. In case of oral administration tablets, apart from those mentioned supports, they can also carry additives such as p. ex. citrate sodium, calcium carbonate and dicalcium phosphate, together with various fillers, such as starch, preferably potato starch, gelatin and Similar. In addition to the preparation of tablets you can add lubricants such as magnesium stearate, sodium lauryl sulfate and talcum powder In the case of aqueous suspensions, the active ingredients, Apart from the aforementioned auxiliary substances, they can be mixed with various flavoring or coloring agents.

       \ newpage
    

In case of parenteral administration you can use solutions of the active ingredients with liquid supports adequate.

For intravenous administration, the dosage is 1-1000 mg per hour, preferably 5-500 mg per hour.

However, it may be convenient to deviate from these amounts, depending on body weight or type of route of application, of the individual response to the medication, of the kind of formulation and the moment or interval in which it has Administration place. Thus, in some cases, a amount less than the prescribed minimum, while in others cases must exceed the upper limit. In case you have to administering larger doses it may be advisable to divide them into Several individual shots per day.

The following formulation examples illustrate the present invention, although without limiting its scope:

       \ vskip1.000000 \ baselineskip
    

Examples of pharmaceutical formulation

200

The finely ground active ingredient is mixed, lactose and a part of corn starch. The mixture is screened, then it is wetted with a solution of polyvinylpyrrolidone in water, Knead, wet granulate and dry. The granulate, the starch of remaining corn and magnesium stearate are screened and mixed each. The mixture is compressed into tablets of shape and size suitable.

201

The finely ground active ingredient is mixed, part of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone The mixture is sieved and with the starch of Remaining corn and water is made a granulate, which is dried and sieved. The sodium carboxymethyl starch and the magnesium stearate, mix and compress into tablets proper shape and size.

202

The active substance is dissolved in water, at pH itself or if necessary at pH 5.5-6.5, and mix with sodium chloride as an isotonic agent. The resulting solution is filter devoid of pyrogens and the filtrate is packaged under aseptic conditions in blisters that are then sterilized and They close by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active principle.

Claims (13)

1. Compounds of the general formula (1), 149 where

quad

R1 is chosen from the group consisting of -NHR c, -NHC (O) R c, -NHC (O) OR c, -NHC (O) NR c R c and -NHC (O) SR c;

quad

R2 is a radical that can be substituted with one or more R 4, chosen from the group consisting of alkyl C 1-6, C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, aryl C 6-10, C 7-16 arylalkyl and 5-10 membered heteroaryl;

quad

R3 is a radical that can be substituted with one or more R e and / or R f, chosen from the group consisting of C 6-10 aryl and heteroaryl of 5-10 members;

quad

R 4 is a radical chosen from the group consisting of R a, R b and R a substituted with one or more R c and / or R b the same or different;

quad

each R a, independently of each other, is chosen from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 alkylalkyl alkyl, C 6-10 aryl, arylalkyl C 7-16, 2-6 heteroalkyl members, 3-8 hetero heterocycloalkyl, 4-14 membered heterocycloalkylalkyl, 5-10 membered heteroaryl and heteroarylalkyl of 6-16 members;

quad

each R b is a suitable and chosen radical independently of each other from the group consisting of = O, -OR c, C 1-3 haloalkyloxy, -OCF 3, = S, -SR c, = NR c, = NOR c, -NR c R c, halogen, -CF 3, -CN, -NC, -OCN, -SCN, -NO, -NO_ {2}, = N_ {{}}, -N_ {3}, -S (O) R c, -S (O) 2 R c, -S (O) 2 OR c, -S (O) NR c R c, -S (O) 2 NR c R c, -OS (O) R c, -OS (O) 2 R c, -OS (O) 2 OR c, -OS (O) 2 NR c R c, -C (O) R c, -C (O) OR c, -C (O) NR c R c, -C (O) N (R g) NR c R c, -C (O) N (R g) OR c, -CN (R g) NR c R c, -OC (O) R c, -OC (O) OR c, -OC (O) NR c R c, -OCN (R g) NR c R c, -N (R g) C (O) R c, -N (R g) C (S) R c, -N (R g) S (O) 2 R c, -N (R g) S (O) 2 NR c R c, -N [S (O) 2] 2 R c, -N (R g) C (O) OR c, -N (R g) C (O) NR c R c and -N (R g) CN (R g) NR c R c;

quad

each R c, independently of each other, is hydrogen or a radical optionally substituted with one or more R d and / or R e same or different, selected from the group formed by C 1-6 alkyl, cycloalkyl C 3-8, cycloalkylalkyl C 4-11, aryl C 6-10, C 7-16 arylalkyl, heteroalkyl of 2-6 members, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkylalkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

quad

each R d, independently of each other, is hydrogen or a radical optionally substituted with one or more R e and / or R f same or different, selected from the group formed by C 1-6 alkyl, cycloalkyl C 3-8, cycloalkylalkyl C 4-11, aryl C 6-10, C 7-16 arylalkyl, heteroalkyl of 2-6 members, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkylalkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

quad

each R e is a suitable and chosen radical independently of each other from the group consisting of = O, -OR f, C 1-3 haloalkyloxy, -OCF 3, = S, -SR f, -NR f, = NOR f, -NR f R f, halogen, -CF 3, -CN, -NC, -OCN, -SCN, -NO, -NO_ {2}, = N_ {{}}, -N_ {3}, -S (O) R f, -S (O) 2 R f, -S (O) 2 OR f, -S (O) NR f R f, -S (O) 2 NR f R f, -OS (O) R f, -OS (O) 2 R f, -OS (O) 2 OR f, -OS (O) 2 NR f R f, -C (O) R f, -C (O) OR f, -C (O) NR f R f, -CN (R g) NR f R f, -OC (O) R f, -OC (O) OR f, -OC (O) NR f R f, -OCN (R g) NR f R f, -N (R g) C (O) R f, -N (R g) C (S) R f, -N (R g) S (O) 2 R c, -N (R g) C (O) OR f, -N (R g) C (O) NR f R f and -N (R g) CN (R g) NR f R f;

quad

each R f, independently of each other, is hydrogen or a radical optionally substituted with one or more R g the same or different, chosen from the group consisting of alkyl C 1-6, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, aryl C 6-10, C 7-16 arylalkyl, 2-6 membered heteroalkyl, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkyl-alkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

quad

each R g, independently of each other, is hydrogen, C 1-6 alkyl, cycloalkyl C 3-8, cycloalkylalkyl C 4-11, aryl C 6-10, C 7-16 arylalkyl, heteroalkyl of 2-6 members, heterocycloalkyl of 3-8 members, 4-14 heterocycloalkylalkyl members, 5-10 member heteroaryl and 6-16 membered heteroarylalkyl;

which can be in the form of their tautomers, of their racemates, of their enantiomers, of their diastereoisomers and their mixtures, as well as, where appropriate, their pharmacologically safe addition salts. 2. Compounds according to claim 1, wherein R 3 is a radical chosen from the group consisting of phenyl, furyl, pyridyl, pyrimidyl and pyrazinyl, substituted, if necessary, with one or more R 4. 3. Compounds according to claim 2, wherein R 3 represents pyridyl. 4. Compounds according to claims 1 to 3, in which R 1 means -NHC (O) R c. 5. Compounds according to claim 4, wherein R 1 represents -NHC (O) CH 3. 6. Compounds of the formula (A) 150 where

quad

X means -CH 3, -OR 4 or -SR 4 Y

quad

And phenyl, 5-10 heteroaryl members or the group -C (O) O and

quad

R y hydrogen, -NO 2 or alkyl C 1-6 and R 4 is defined as previously.

7. Compounds according to claim 6, wherein R 4 represents C 1-6 alkyl. 8. Compounds of the general formula (A) according to the claim 6 or 7, for use as synthesis intermediates. 9. Compounds, or their salts pharmaceutically active, according to claims 1 to 5, as medicines. 10. Compounds, or their salts pharmaceutically active, according to claims 1 to 5, to produce a antiproliferative action medication. 11. Pharmaceutical preparations as a principle active contain one or more compounds of the general formula (1) according to one of claims 1 to 5, or its salts physiologically compatible, combined, if necessary, with auxiliary substances and / or usual supports. 12. Use of compounds of the general formula (1) according to one of claims 1 to 5, to prepare a medicine intended for the treatment or prevention of cancer. 13. Pharmaceutical preparation containing a compound of the general formula (1) according to one of the claims 1 to 5 and at least one other active substance, cytostatic or cytotoxic, of a formula other than (1), if necessary, in the form of their tautomers, racemates, enantiomers, diastereoisomers and mixtures, as well as, if necessary, of their addition salts pharmacologically safe.